1. Field of the Invention
The present invention relates to the field of retinal disorders. More specifically, the invention relates to the treatment of disorders involving the accumulation of drusen, such as dry age-related macular degeneration.
2. Description of the Related Art
Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with an incidence of about 20% in adults 65 years of age increasing to 37% in individuals 75 years or older. Non-exudative (dry) AMD is characterized by drusen accumulation and atrophy of rod and cone photoreceptors in the outer retina, retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaris; while exudative AMD leads to choroidal neovascularization (Green and Enger, Ophthalmol, 100:1519-35, 1993; Green et al., Ophthalmol, 92:615-27, 1985; Green and Key, Trans Am Ophthalmol Soc, 75:180-254, 1977; Bressler et al., Retina, 14:130-42, 1994; Schneider et al., Retina, 18:242-50, 1998; Green and Kuchle (1997). In: Yannuzzi, L. A., Flower, R. W., Slakter, J. S. (Eds.) Indocyanine green angiography. St. Louis: Mosby, p. 151-6). Retinitis pigmentosa (RP) represents a group of hereditary dystrophies characterized by rod degeneration with secondary atrophy of cone photoreceptors and underlying pigment epithelium. (Pruett, Trans Am Ophthalmol Soc, 81:693-735, 1983; Heckenlively, Trans Am Ophthalmol Soc, 85:438-470, 1987; Pagon, Sur Ophthalmol, 33:137-177, 1988; Berson, Invest Ophthalmol Vis Sci, 34:1659-1676, 1993; Nickells and Zack, Ophthalmic Genet, 17:145-65, 1996). The pathogenesis of retinal degenerative diseases, such as AMD and RP, is multifaceted and can be triggered by environmental factors in normal individuals or in those who are genetically predisposed. To date more than 100 genes have been mapped or cloned that may be associated with various outer retinal degenerations.
Early stages of macular degeneration are typically treated by combinations of antioxidants or anti-inflammatory agents whose efficacy has not been demonstrated in the clinic. Advanced stages of macular degeneration that lead to severe vision loss are treated either by surgical removal of membranes from the subretinal space, laser photocoagulation, photodynamic therapy, and most recently with VEGF blockers in patients with exudative AMD. No approved treatments are available for the advanced form of dry AMD known as Geographic Atrophy. Laser treatment is also used in the treatment of diabetic retinopathy. It is important to note that both laser photocoagulation of the retina and surgical excision of subretinal membranes or intravitreal membranes results in the destruction of viable retinal neurons.
One obstacle to obtaining regulatory approval for the marketing of treatments for retinal disorders is the lengthy clinical trials that are required. Although inhibition and/or reversion of angiogenesis and/or neovascularization can be illustrated in animal models where the animals are sacrificed and their eye tissues analyzed, it is difficult to determine whether angiogenesis or neovascularization has been effectively halted or reversed in the eyes of live patients. Therefore, in order to establish effectiveness of inhibitors of angiogenesis or neovascularization, for example, it is necessary to show an improvement in visual acuity, which often takes one to two years to manifest meaningfully.
Drusen deposits have been shown to be a significant risk factor for the development of dry AMD. In fact, the underlying cause of dry AMD is thought to be related to drusen deposits. Dry AMD leads to wet AMD or geographic atrophy in approximately 10%-15% of the patient population. Geographic atrophy is characterized by classic lesions in dry AMD. The lesions that lead to geographic atrophy are known as drusen. Drusen deposits are known to be composed of proteins and lipids (i.e., phospholipids, neutral lipids, cerebrosides, gangliosides, numerous other proteins, etc) that are derived from systemic, choriocapillaries and retinal sources. There is currently no approved treatment for halting or reversing loss of vision resulting from dry AMD or geographic atrophy.
Cyclodextrins have long been known to be superb solubilizing agents through their ability to complex with lipophilic materials and some proteins to form inclusion complexes. For example, (1) U.S. Pat. No. 4,533,637 discusses the use of cyclodextrins to make inclusion complexes with lipophilic materials (lipids) to make a low-serum culture media; (2) U.S. Pat. No. 4,727,064 discusses the use of cyclodextrins to solubilize drugs in inclusion complexes; and (3) U.S. Pat. Nos. 4,983,586 and 5,024,998 discuss the use of cyclodextrins (in concentrations of 20-50%) to solubilize (as inclusion complexes) lipophilic drugs for injection. None of these references discuss the delivery of therapeutic amounts of cyclodextrins into the subTenons area of the eye, in the absence of inclusion complexes.
Cyclodextrins have been increasingly used in pharmaceutical formulations, in low concentrations, as a solubilizing or penetrating agent. For example, U.S. Pat. Nos. 5,919,813 and 6,028,099 (de Juan et al.) are directed to the treatment of diabetic retinopathy or choroidal neovascularization via administration of protein tyrosine kinase inhibitors, such as genistein or derivatives thereof. In describing the pharmaceutical compositions for use in the claimed treatment methods, the applicants state that the PTK inhibitor can be formulated as cyclodextrin inclusion complexes, among other types of suggested excipients for pharmaceutical formulations. These patents do not suggest the use of cyclodextrins in therapeutically effective amounts as active ingredients for the solubilization of drusen or the treatment of dry AMD.
U.S. Pat. Nos. 5,747,544 and 5,854,015 (Garnett et al.) describe a method for preparing pure stereoisomers of zeaxanthin and their use in the treatment of AMD. The specification explains that it may be desirable to administer the zeaxanthin formulations via injection in some patients, which can be carried out using implants or injectable carrier liquids. In the discussion, it is stated that “carrier formulations that are used for injection of hydrophobic compounds typically include water, a buffering agent, and an organic compound having a plurality of hydroxyl groups, such as propylene glycol or dextran or cyclodextrin compounds.” Again, the cyclodextrin is clearly used as an excipient in these types of carrier formulations. It is not contemplated that cyclodextrin itself could be administered in therapeutically effective amounts as an active ingredient for the solubilization of drusen or the treatment of dry AMD.
Li et al. (IOVS, 32(11):2898-2905 (1991)) showed that topical applications of a composition containing sulfated cyclodextrins with angiostatic steroids enhance the ability of the angiostatic corticosteroids to inhibit angiogenesis. In these compositions, the cyclodextrins were used as excipients and were not present in therapeutically effective amounts.
All of the therapies described above utilize cyclodextrins solely as an excipient in pharmaceutical formulations containing other types of small molecule active ingredients for the treatment of AMD. None of the publications discussed suggest the use of cyclodextrins in therapeutically effective amounts as an active ingredient for the solubilization of drusen and/or the treatment of dry AMD. Furthermore, measurement of effectiveness of those therapies often requires lengthy clinical trials in order to determine whether visual acuity has been improved.
What is needed is a therapy for dry AMD that targets the large, soft drusen that accumulate in the eyes of patients suffering from, or at risk for developing, dry AMD. Moreover, it is desirable to be able to discern quickly, i.e., within a matter of weeks or months, rather than years, whether such a therapy is effectively eliminating such drusen deposits, thereby decreasing the risk of vision loss due to dry AMD.